5-benzyl pyrimidines intermediate therefore, and method

ABSTRACT

Compounds comprising selected N-substituted Beta -amino- Alpha -benzyl-acrylonitriles and methods of preparing said compounds substantially free from the corresponding benzalacrylonitrile. The compounds are useful as intermediates in the preparation of antibacterial and antimalerial agents.

United States Patent [191 Cresswell et al.

Dec. 3, 1974 S-BENZYL PYRIMIDINES INTERMEDIATE THEREFORE, AND METHOD Inventors: Ronald M. Cresswell, Scarsdale;

John W. Mentha, Hartsdale; Russell L. Seaman, Chappaqua, all of NY.

Assignee: Burroughs Wellcome Co., Research Triangle Park, NC.

Filed: June 2, 1972 App]. No.: 259,338

Related US. Application Data Division of Ser. No. 16,606, March 4, 1970, Pat. No. 3,694,512.

Foreign Application Priority Data Mar. 6, 1969 Great Britain 11908/69 Mar. 6, 1969 Great Britain 11909/69 May 16, 1969 Great Britain 25171/69 June 13, 1969 Great Britain 30247/69 U.S. C1 260/240 R, 424/251, 260/256.4 N, 260/465 E, 260/465 F, 260/465 K, 260/592, 260/607 A Int. Cl. C07c 121/42 Field of Search 260/240 R, 415 E England 260/256.4

OTHER PUBLICATIONS Houben-Weyl, Methoden der O'rganischcn Chemie. Vol. 11/1, pages 248 to 266, George Thieme Verlag. sarwsrm n Primary Examiner-John D. Randolph Attorney, Agent, or Firm-Dike, Bronstein, Roberts, Cushman & Pfund [57] ABSTRACT Compounds comprising selected N-substituted ,B-amino-a-benzyl-acrylonitriles and methods of me paring said compounds substantially free from the corresponding benzalacrylonitrile.

The compounds are useful as intermediates in the preparation of antibacterial and antimalerial agents.

13 Claims, No Drawings This is a division, of application Ser. No. 16,606, filed on Mar. 4, 1970, now US. Pat. No. 3,694,512.

This invention relates to improved methods of preparing S-benzylpyrimidines and more particularly is related to a class of stable a-benzylacrylonitrile intermediates, and to methods of making such compounds.

2,4,-Diamino--benzylpyrimidines possess both antimalarial and antibacterial activities (1. Am. Chem. Soc., 1951, 73, 3758). Maximal antibacterial activity is found among derivatives which bear electron donating substituents in the benzene nucleus and are unsubstituted in the 6th position of the pyrimidine moiety. 2,4- Diamino-5-( 3 ,4',5 -trimethoxybenzyl) pyrimidine or trimethoprim (U.S. Pat. No. 2,909,522) has a moderately broad antibacterial spectrum which includes many of the Gram-positive species but it is also active against species of the genus Proteus. in common with other 2,4-diaminopyrimidines it is a competitor of folic and folinic acids in microorganisms which require these nutrilites, and it can be shown to inhibit dihydrofolate reductase in Streptococcus faecalis. A strong potentia tive effect is observed when the ,drug is administered in combination with sulphonamides as a consequence of the sequential blockade of the biochemical pathway which leads to the de novo synthesis of coenzymes F. This potentiation may be demonstrated both in vitro and in experimental infections in mice with Staphyloccoccus and Proteus species.

2,4-Diamino-5-benzylpyrimidines, which includes trimethoprim and 2,4-diamino-5-( 3 ',4-dime thoxybenzyl)pyrimidine or diaveridine and 2,4-diamino-5- (3 ',4'-dimethoxy-S-bromobenzyl)pyrimidine (U.S. Pat. No. 2,658,897), may be administered orally at a dose of 1 mg/kg to 30 mg/kg per day.

Preferably these compounds are administered in tablet form to a mammal being treated, and trimethoprim may advantageously be combined with sulphamethoxazole against certain respiratory infections. A further example of this class is 2,4-diamino-5-(2'-methyl-4',5'- dimethoxybcnzyl)pyrimidine (ormetoprim), which has been reported to show antibacterial activity, and also has coccidiostatic properties when combined with sulphadimethoxine.

A new route was developed some years ago for the preparation of 2,4-diamino-5-benzylpyrimidines (see Stenbuck,Baltzly and Hood, J. Org. Chem., 1963, 28, 1983 and British Patent No. 957,797). This route comprises the steps of (i) condensing an aromatic aldehyde with a B-substituted propionitrile in the presence of both an alcohol as solvent and a strong base to give a mixture of isomers of formulae (la) and (lb) respectively:

ON ArCHO GHQ-ON ArCH=C my omz I m) 0N A1-cru-o um. 1m

wherein Ar is an optionally substituted phenyl group, Y is an alkoxy, thioalkyl or dialkylamino group, and z is the group Y or is an alkoxy group derived from the solvent alcohol; and (ii) reacting either the pure benzal' isomer (la) or a mixture of benzal and benzyl isomers (la) and (lb) respectively with guanidine to give a S-benzylpyrimidine of formula Although it was known that the intermediate product obtained in the first step was a mixture of isomers of formulae (la) and (h), only the (la) benzal isomer could be isolated in a crystalline form after some purification steps. The two isomers were assumed to be in equilibrium with each other when prepared under alkaline conditions and further reacted with guanidine according to the aforesaid disclosures, but it was not clearly established which of the isomers was primarily interacting in the second step. In many cases this method affords acceptable yields but in certain instances extensive losses (up to about half the material used) ensue from formation of yellow polymers.

The further conversion of composite mixtures of derivatives and isomers according to British Patent No.

957,797, afforded the required 2,4-diamino-5-benzylpyrimidines only in yields between 25 percent and 45 percent, and in view of the importance of the final products and the difficulties with by-products and impurities, alternative methods were also explored by var ious investigators. For instance, the specification of South African Pat. application No. 65/5794 discloses a process comprising the steps of (a) reacting acetylthymine with Nbromosuccinimide to form acetylbromothymine, (b) condensing the product with a substituted benzene, (c) reacting the product with a halogenating agent, and (d) aminating the halogeno deriva tive. However, this process suffers from the disadvantages that acetylbromothymine is expensive to make, condensation with the benzene compound does not provide the further intermediate in a high yield, and the last stage requires operation under pressure and usually results in an equilibrium state with consequent poor yields. Altogether the process requires four stages to obtain the final product, and none of the stages is particularly advantageous.

Subsequent developments showed that the polymer formation obtained when operating the process described in the specification of British Pat. No. 957,797, could be prevented or reduced in cases of B-alkoxyderivatives of compounds (la) and (lb) by temporarily saturating the double bond with excess alkoxide in alcohol.

This provides the corresponding acetal of formula ll), for instance, according to the reaction outlined below:

ON Ar CH: C

CH: OMe

: ArCHzC C H Me MeOH excess NaOMe AlCHl-GH C H( 0 Me):

When the acetal (II) is subsequently treated with guanidine in alcoholic solution, the alkaline condition is thought to catalyse the reconstitution of the double bond, initially in the form of (I'b), and the intermediate can thus react with guanidine to give the desired 5- benzylpyrimidine.

Acetals of formula (II) may also be prepared by condensing the corresponding aromatic aldehyde with a 3,3-dialkoxy-propionitrile and reducing, preferably catalytically, the 3,3-dialkoxy-2-benzalpropionitrile intermediate so obtained. (See US. Pat. No. 3,487,083).

The aforesaid British Patent No. 957,797 also'describes (Example 14) the reaction of veratraldehyde with B-dimethylaminopropionitrile in the presence of sodium in ethanol to give a mixture of B-dime thylaminoveratralnitrile (III) and B-ethoxyveratralnitrile (IV) in a 32 percent yield.

MeO

/CN MBO CH=C\ CHzNMGz (III) MeO ON MeO CH: O

CHzO Et It is stated in the Example that this mixture was subsequently cyclised with guanidine to give 2,4-diamino-5- (3',4'-dimethoxy-benzyl)-pyrimidine. It is to be noted that both the compounds (III) and (IV) above are benzal derivatives.

It has now been found that N-substituted B-amino-abenzylacrylonitriles of the configuration of formula benzylacrylonitriles can be converted into benzylpyrimidines or into other benzyl derivatives, which may be used as preferred for the preparation of benzylpyrimidines or other heterocyclic ring systems.

According to the present invention in' one aspect therefore there is provided an N-substituted-B-aminoa-benzylacrylonitrile compound of the formula (V), in a form substantially free from contamination with the B-amino-a-benzylidenepropionitrile isomer. In particular the contamination with the benzal isomer is normally substantially below 10 percent, taken as a percentage of the amount of compound of formula (V), and preferably below 5 or, still better, below 2 percent. Usually the best methods for making the compound of formula (V) provide the product with less than 0.5 percent contamination and frequently no benzal isomer can be detected at all with analytical methods sensitive to even as low as 0.33 percent admixture. It has, on the other hand, been observed that contamination at or above the 10 percent level adversely affects the yield and quality of the final benzylpyrimidine product, and the appearance of purple or yellow discolourisation may aggravate the difficulties, especially isolation in a pure form, an essential requirement when the product is to be used clinically, there therefore being necessary many tedious, time-consuming and accordingly expensive purification steps.

As previously defined Ar is an optionally substituted phenyl group in formula (V). The B-amino group NR R is an aliphatic, heterocyclic or aromatic amino group, and can have only one hydrogen atom for R and R In general it may be stated that, as a free amine, I-INR R is preferred to have a pKa value not lower than about 0, and also most preferably not higher than about 6.

In particular, it is especially preferred that the NR R group is a primary anilino group (e.g. aniline, o and p -toluidine p-anisidine,p-chloroaniline, 2,5 and 3,4 dichloroanilines). The phenyl ring of this group may be optionally substituted with one or more substituents such as halogen atoms, and alkyl and alkoxy groups, but the unsubstituted anilino group is, however, particularly preferred.

The NR R group may also be a primary amino group other than the aforesaid primary anilino group, such as a monoalkylamino, benzylamino, or naphthylamino, preferably a-B-naphthylamino group; or may be a secondary amino group, such as a dialkylamino,N-ethylanilino,pyr'rolidino, piperidino, N-methylanilino or a piperazino group, or most preferably the morpholino group.

In particular the invention provides compounds of formula (VIII), in a form substantially free from contamination with the a-amino-4-benzylidene- P QP witt le ,ieqme a h eiabe9 e9 d= R1 R CN CH1 0 R R OIL-N R4 V R (VIII) wherein the group -NR R is as hereinbefore defined with reference to a compound of formula (V), and R, R, R and R are the same or different and each is a hydrogen or a halogen atom, an alkyl, alkoxy, or benzyloxy group, or R and R taken together may be a methylendioxy group when both R and R are hydrogen atoms. Preferably the whole amino group NR R comprises not more than 12 carbon atoms.

All of the above compounds of formula VIII are convertible to benzyl pyrimidines and such pyrimidines are useful as antibacterials.

In formulae (V) and (VIII), and elsewhere in this application each of the alkyl or alkoxy groups in the substituents may have from I to 4 carbon atoms, e.g. they may be methyl, ethyl, propyl or butyl groups, including normal, iso or tertiary branched forms, and corresponding alkoxy groups. Each of the halogen atoms may be represented by a chlorine, bromine, fluorine or iodine atom.

More particularly the para-position of the phenyl group may be substituted with a benzyloxy, but preferably an alkoxy group, such as a methoxy group, especially with a similar or identical alkoxy substitution at one or advantageously both adjacent-positions on the phenyl ring. As another possiblity alkoxy, e.g. methoxy substitution, in such positions may be combined with an alkyl, 'e.g. methyl, substitution at the ortho-position of the phenyl group.

The compounds of formulae V (or VIII) fall into two classes A and B dependent on their reactivity towards guanidine. V

R2 ON Data R; R CHNHPh Wherein Ph is an aryl group of 6 to 12 carbon atoms which may be substituted in one, two, or three positions with lower alkyl, lower alkoxyl, and halogen, preferably chlorine and where the R R are defined as previously and lower alkyl halogen and lower alkoxyl are as previously defined. Compounds of type VIII A react readily with guanidine in e.g. solvent lower alcohol solution to form 2,4-diamino-S-benzylpyrimidines in good yield. Advantageously the reaction is conducted at the reflux temperature of the solution, but useful rates are found at lower temperatures down to room The compounds according to formula (V) or (VIII), respectively, may be prepared by a wide variety of methods. The actual choice between these methods in any particular instance depends primarily on the reactivity of the compound obtained, and the further processing to which it may be subjected to provide compounds such as pyrimidines of clinical utility, the further processing being itself governed to a great extent by the nature of the amino group NR R this acting as a leaving group in the further reactions.

Compounds according to formula (V) or (VIII) can be prepared by a method provided by the present invention, which comprises reacting the corresponding benzaldehyde with the corresponding B-aminopropionitrile in the presence of a base in a polar aprotic solvent compatible with and dissolving both reactants.

' culated on the aldehyde used, particularly at temperatemperatures. These compounds are consequently pre-' ferred.

The compounds of formula VIII 8 wherein R is alkyl or aryl and R is alkyl and may also be hydrogen when R is alkyl and NR -R VIIIB may also be cyclic amino such as morpholino, piperidino and pyrrolidino, react only slowly with guanidine base, so that periods of 1-2 weeks would be required 1 the tures above 60C, preferably between C and C. For instance, very good yields have been obtained in this manner using dimethylsulphoxide as the solvent.

Very satisfactory yields have also been obtained, for instance, with B-primary anilino-substituted compounds with 0.5 to 2 molar equivalents of the base at room (about 20 C) or slightly elevated temperature up to about 60C in the solvent. Dimethylsulphoxide may be replaced under these conditions as well as by other polar aprotic solvents, expecially hexamethylphosphoramide. It has been found most advantageous to use t-butoxide as the base in the form of the potassium salt in dimethylsulphoxide for the preparation of B-anilinosubstituted compounds whilst, for instance, the B-morpholino-analogue may be preferred to be formed in the presence of sodium methoxide in the same medium.

Yet further methods provided by the present invention may be used to obtain selected or preferred ranges of compounds within the scope of formula (V) or (VIII). Accordingly, a method is provided for preparing such compounds, wherein the B-amino group NR*"R is a primary anilino group optionally substituted in the phenyl ring, as hereinbefore defined, which comprises reacting the corresponding benzaldehyde with corresponding B-primary-anilino-propionitrile. Preferably the reaction is carried out in a polar nonaprotic solvent compatible with anddissolving the reactants in the presence of a base. Conveniently an alkanol may be used for the purpose, and the reaction is desirably carried out at elevated temperatures, say between 40 and 80 C. The preferred alkanol is methanol, particularly when the reactant benzaldehyde is.

tion to the other preparatory methods are again appli- 30 C. The solvent may be an alkanol, such as methanol,

ethanol or isopropanol, or most conveniently a polar aprotic solvent such as exemplified above. The base is preferably sufficiently strong on its own for a significant amount of the sulphone or sulphoxide reactant to be converted into the anionic form. Again hydroxides or alkoxides, preferably methoxide or t-butoxide, in the form of an alkali metal salt, have been found very convenient for the purpose. The method is especially suitable for making Type VIII A.

The required B-hydroxy-B-phenethylmethylsulphone or sulphoxide for the above method, may conveniently be provided by a process described in the provisional specification of British Pat. application No. 25171 /69. This process comprises the steps of reacting an appropriatelyqsubstituted benzoic acid ester with dimethyl sulphone or dimethyl sulphoxide preferably in the presence of a base, and selectively reducing the so obtained acetophenone methylsulphone or methylsulphinyl derivative, for instance, with a suitable reducing agent e.g. borohydride or with aluminum isopropoxide.

The above defined group of B-primary-anilino-abenzyl-acrylonitriles can also be prepared by a method which comprises reacting the corresponding aniline, generally in the form of an acid addition salt, with a compound of formula (V) or (VIII) carrying an amino substituent which has, as the free amine HNR R a pKa value higher by at least about 3 to 4 units than that of the aniline used for the reaction. For instance, a morpholino substituent may, in this manner, be directly replaced by an anilino substituent, morpholine having a pKa value of about 8.6 and the aniline generally about 4 to 5. Preferably the reaction is carried in a polar nonaqueous solvent system, for instance, ethanol or glacial acetic acid, at reflux temperatures.

The compounds VIII A are also preparable by reaction of Pi'INH with B-hydroxy-a-benzylacrylonitriles:

PhNHz CHOH=C-CN R X VIII'A 6H2 R2 i The product may then be extracted with an organic solvent from the aqueous medium and reacted with a different amine to obtain a compound according to formula (V) or (VIII). There is little or no tendency to isomerize to the benzal form during these manipula- Such a conversion from one amino derivative to'another may be achieved in a very high yield, in many instances above percent in both steps, and the product so obtained can be reacted to form other materials such as benzylpyrimidines in a quality and yield often even better than that provided by using the original ,B-aminod r v t ve In addition, this method may be very advantageous for preparing certain B-amino-a-benzylacrylonitriles, especially in cases where the NR R group is basic but only weakly basic anilino group, e.g. p-chloro-anilino. In such instances, there are sometimes difficulties in preparing the corresponding B-anilino-propionionitrile for reaction with the benzaldehyde.

The ,B-hydroxy-a-benzylacrylonitriles may also be used as intermediates for further syntheses, and can, for instance, be alkylated to provide the appropriate B-alkoxy-a benzylacrylonitrile, substantially free from the benzal isomer or acetal. The benzyl compound so formed and in such purity is also eminently suitable as a starting material for the synthesis of benzylpyrimidines, and provides the latter in a substantially increased yield and at a better quality than the mixture of benzyl and benzal isomers, or the benzal isomer alone, of the method described in British Pat. No. 957,797.

Compounds according to formula (V) or (VIII), wherein the ,B-amino group l lR"R is a primary amino group other than anilino, or is a secondary amino group, can also be prepared according to the present invention by reacting the corresponding B-alkoxy-abenzylidenepropionitrile with an excess of the appropriate amine in the presence of a base in an alkanol. Suitable bases are again those already listed for other methods. Preferably the base is the alkoxide corresponding to the solvent. For instance, a B-methoxide-abenzylidenepropionitrile may be so converted with morpholine, in methanol containing sodium methoxide, to the corresponding B-morpholino-a-benzylacrylonitrile.

The above group of compounds according to formula (V) or (VIII), wherein the B-amino-group NR R is other than the anilino group, can moreover'be prepared according to the present invention by isomerising the corresponding B-amino-a-benzylidenepropionitrile isomer with a base in a polar aprotic solvent. Under these conditions the benzal is isomerised into the benzyl form, there appearing to be little or no benzal isomer after the process. Suitable aprotic polar solvents and bases are as hereinbefore described with reference to other reactions, and the most preferred solvent is again dimethylsulphoxide and the most convenient bases are the methoxide and t-butoxide anions. Normally there is at least about 0.01, and preferably about 0.1 molar concentration of base present in the solvent, and often not more than about 1 molar concentration, though as high as 2 or even 4 molar concentrations may be used. The quantity of solvent is not critical though there is preferably sufficient throughout the isomerisation to dissolve the nitrile. The isomerisation can be effected at room temperature but is most propionitriles, in particular to those having a 3,4-'

dimethoxy or 3,4,5-trimethoxy-benzylidene group.

The starting benzal isomer, i.e. the appropriate B-amino-a-benzylidene-propionitrile, for the purposes of the above reaction, can advantageously be prepared by reacting the corresponding benzaldehyde with the corresponding B-aminopropionitrile in an alkanol in the presence of a catalytic amount of a base, in the sense hereinbefore used in the present specification, which means an effective quantity of less than 0.3 molar equivalent calculated on the aldehyde reagent.

Alkanols in this reaction are generally lower alkanols, having from I to 4 carbon atoms, methanol being particularly preferred. Suitable bases are again those already suggested in connection with base catalysed condensation reactions, but methoxides and tert.- butoxides, particularly the former, are preferred for the present purpose. Best results may be obtained at elevated temperatures, and it is particularly preferred to carry out the reaction at reflux temperatures.

As already indicated, the optimum route for preparing any particular compound according to formula (V) or (VIII) may comprise a combination of a number of the above processing possibilities, depending primarily on the type of amino NR R group required. For instance, ,B-primary-anilino-a-3,4,5'-trimethoxybenzylacrylonitrile has certain especial advantages as an intermediate for the preparation of trimethoprim.

Thus, the reaction of guanidine with B-primary-anilinoa-benzylacrylonitriles generally proceeds appreciably faster than that with other B-amino derivatives as defined by formula (V) or (VIII).

The B-anilino-intermediate can moreover be produced readily without any benzal isomer detectable by standard analytical methods, and can be further processed to 2,4-diamino--benzylpyrimidines in a very high yield there being little or no polymer formation at all. It is more noteworthy than the reaction with guandine is readily effected under mild conditions, and both the preparation of intermediate and the further processing may be completed within hours rather than weeks.

Whilst B-primary-anilino-a-benzylacrylonitriles may be readily prepared by a wide variety of advantageous methods, the choice in any particular instance depends partly upon the availability of the starting material, and. for intance, B-anilino-propionitrile, when prepared from aniline and acrylonitrile, usually requires isolation and purification before use. In contrast, the corresponding B-morpholinopropionitrile can be readily formed and need not be isolated. Furthermore, in cases of trimethoxy-substituted benzyl derivatives, and base catalysed reactions, the cheaper and more widely available sodium methodide is preferred for morpholino-den'vatives, whilst the more expensive potassium t-butoxide generally gives best results for anilino-compounds. It may therefore on occasion be advantageous to prepare the morpholino-intermediate first and convert this into the corresponding anilino derivative to obtain optimum results.

According to the present invention in a further aspect there is provided a method of preparing 2,4- diamino-S-benzylpyrimidines as shown in formula IX which are useful as antibacterials, wherein the benzyl group comprises an optionally substituted phenyl group, by reacting the corresponding B-amino-abenzylacrylonitrile of formula (V), substantially free from contamination with the B-amino-a-benzylidenepropionitrile isomer, as hereinbefore defined, with guanidine. In particular a method is provided of preparing a compound of formula (IX) which comprises reacting a compound of formula (VIII) substantially free from contamination with the ,8-amino-a-benzylidenepropionitrile isomer, as hereinbefore defined, with guanidine; in formula (IX) R, R R and R are as defined for formula (VIII). It has been found that the pyrimidine products are obtained in a satisfactorily high yield as well as without contamination with polymers and coloured impurities. These aspects are of critical importance as indicated hereinbefore, since contemporary requirements for the purity of pharmaceutical products are very stringent and the products must be manufactured in a very pure form and, of course, at a reasonable cost. Both these necessities are now more readily attainable, as a result of the present invention, for the benzylpyrimidines.

To obtain S-benzylpyrimidihes [having particularly For the purposes of obtaiing S-benzylpyrimidines or in particular those of formula (IX) preferably having the above mentioned specific substituents, the appropriate B-anilinoderivatives have been found particularly useful. Advantageously such an amine is reacted with quanidine, conveniently in a lower alcohol solvent, for example, methanol, ethanol, or isopropanol, at elevated temperatures. It is particularly preferred that the reaction is carrier out at the reflux temperature of the reaction mixture, but useful routes are found at temperatures down to room temperatures. It has been found specifically that the reaction takes place very readily, taking hours rather than weeks for completion.

Although the reactivity with quanidine, or B-aminoa-benzylacrylonitriles of formula (V) or (VIII), other than those having a B-primary-anilino group, such as the morpholino derivatives is lower, particularly in alkanols, it has been found that this can be increaased and the yield substantially improved if the guanidine is employed in the form of the carbonate in a polar aprotic solvent, as hereinbefore described with reference to other methods, e.g. especially dimethylsulphoxide or hexamethylphosphoramide. Best results have been obtained in these particular cases with dimethylsulphoxide at or near C; and, if the previous reaction step has also been carried out in the same medium the -Bamino-a-benzylacrylonitrile intermediate need not be isolated, although isolation is usually preferred since purer benzylpyrimidine is obtained in this manner.

All end products provided in the above manner have either antibacterial activity or potentiating properties,

although the degree of such activity and potentiating effect may vary according to substitution and the purpose for which these compounds are employed. Moreover, the products may themselves be used as starting materials to produce other derivatives and analogues by further reactions with functional groups thereon. Thus ben zyloxy-benzyl-derivatives may, for instance be converted into the corresponding hydroxy-benzylderivatives by hydrogenation, or any hydroxy-benzylderivatives alkylated to provide the required alkoxy-benzyl-substituted compounds.

According to the present invention, therefore, there are provided:

i. N-substituted-B-amino-a-benzylacrylonitrile compounds according to formula (V), or, in particular, formula (VIII), substantially free from contamination with B-amino-abenzylidenepropionitrile, as hereinbefore described;

ii. the various methods of preparing B-amino-abenzylacrylonitriles of formula (V) or (VIII), as hereinbefore described;

iii. the various methods of converting such a B-aminoa-benzylacrylonitrile into a different compound of the same class with respect of the B-aminosubstitution, as hereinbefore described;

iv. N-substituted B-amino-a-benzylacrylonitriles whenever prepared by a method defined under either of paragraphs (ii) and (iii), as hereinbefore described;

v. B-hydroxy-a-benzylacrylonitriles substantially free from contamination with isomers, as hereinbefore described; 7

vi. the methods of preparing the compounds defined under paragraph (v);

vii. the methods of preparing S-benzylpyrimidines by using compounds or products of methods, according to any one of paragraphs (i) to (vi), as hereinbefore described; g

viii. S-benzylpyrimides whenever prepared by a method including steps according to any one of paragraphs (ii), (iii), (vi) and (vii).

The present invention, in each of the above aspects, is particularly preferred when the phenyl group is a 3,4- dimethoxy, 3,4,5-trimethoxy or 2-methy1-4,5- dimethoxy group, since there are then produced the especially valuable compounds diaveridine, trimethoprim or ormetoprim, or the respective intermediates therefor.

The following Examples illustrate the invention:

EXAMPLE 1 3,4,S-Trimethoxybenzaldehyde (98g. B-anilinopropionitrile (85g), and dimethylsulfoxide (175 ml.) were heated together to 125C. A solution of sodium methylate (5g.) in methanol (50ml.) was gradually added and in so doing the reaction temperature rose to 130C, and this temperature was maintained for a further 17 minutes. The reaction mixture was chilled; water was added to a persistent haze; seeds of ,B-anilinoa-3,4,5- trimethoxybenzylacrylonitrile were added; and the mixture was stirred at 25C until precipitation was copious. Additional water (400ml.) was added, and the product was collected by filtration and reslurried in ice water (600ml. The collection and reslurry procedures were repeated using cold (-5C) denatured alcohol (320ml.), and the crystalline B-anilino- (1-3,4,5-

-trimethoxybenzylacrylonitrile was finally collected;

washed with cold denatured alcohol (40ml.), and hexane (100ml.). Wt.=115g. (71 percent; 98 percent pure by UV. assay) m.p. 132 133C (recrystallised from methanol).

EXAMPLE 2 treated as in Example 1 to give B-anilino-a-3,4,5-

trimethoxybenzylacrylonitrile as a crystalline solid. Wt.=57 g. percent).

EXAMPLE. 3

3,4,5-Trimethoxybenzaldehyde (117.5 g; 0.6 mole), B-anilinopropionitrile (101 g.; 0.69 mole), and dry distilled dimethylsulfoxide (348 ml.) were heated together to 40C until solution was complete. The mixture was chilled to 12C and a solution of potassium t-butoxide in t-butanol (13.6 percent; 491 ,ml.; 0.6 mole) was added over the course of about 10 min, such that the final temperature was about 30C. The temperature was raised to 40C and maintained for one hour. t- Butanol was then stripped from the reaction using vacuum to a final pot, temperature of 55C. The residue was chilled to 30C and water 100 ml.) and denatured ethanol (50 ml.) added. The mixture was seeded and after obvious crystallisation more ice/water (500 ml.) and denatured ethanol ml.) were added. When the final temperature of the mixture was 510C the crys-- talline B-anilino-a-3,4,5trimethoxybenzylacrylonitrile was collected, and washed with a mixture of cold water/denatured ethanol (:15; 600 ml.). WF18L7 g. (94 percent pure by UV. assay; yield 88 percent).

EXAMPLE 4 3,4-dimethoxybenzaldehyde (88 g.), B-anilinopropionitrile (82.5 g-), dimethylsulfoxide (160 ml.), and sodium methylate were heated together at 95C for 2 /2 hr. The reaction mixture was then chilled to 25C and diluted with isopropyl alcohol (40 ml.) and water.- When crystallization was obvious further water (200 ml.) was added. The mixture was cooled to 5C and crystalline B-anilino-a-3,4 dimethoxybenzylacrylonitrile was collected and washed with cold water/isopropyl alcohol (1:1). Wt.=99 g. (61 percent) m.p. 153154C (recrystallised from denatured alcohol).

EXAMPLE 5 Piperonaldehyde (45 g.), B-anilinopropionitrile (52 g.) and dimethylsulfoxide (96 ml.) were heated to-.

gether to 120C and a solution of sodium methylate (2.5 g.) in methanol (12 ml.) was added over a 5 min. period. The temperature was maintained at 1 15120C for 1 hr. and the mixture was then poured into ice-water. The resulting gum was collected by decantation and was likewise washed with water (2 X 100 ml. Methanol (100-m1.) was then added and the mixture was heated until solution was complete. Cooling to 5C gave B-anilino-a-piperonylacrylonitrile as a crystalline solid which was collected, and washed with cold methanol, ether, and pentane. Wt.=45 g. (54 percent) m.p. 150.5-151C (recrystallised from methanol).

EXAMPLE 5a The procedure of Example 3 was repeated using 3,4- dimethoxy-S-brombenzaldehyde (78 g.) and gave B-anilino-a-3 ,4-dimethoxy-5-bromobenzylacrylonitrile. Wt.=62 g. (52 percent) m.p. 151154C.

EXAMPLE 6 Sodium methylate (5.4 g.) in t-butanol (50 ml.) was slowly treated with a solution of 3,4,5-trimethoxybenzaldehyde g.) B-(p-methylanilino)-propionitrile (17.5 g.) in dimethylsulfoxide (50 ml.). The mixture was stirred at 45C for one hour and the alcohol then removed in vacuo (bath temperature It 50C). The mixture was poured into ice-water and the crude product collected and recrystallised from methanol to give B-(p-methylanilino)-a-'3,4,5-trimethoxybenzylacrylonitrile. Wt.= g. (89%) mp. l50-151C (recrystallised from methanol).

EXAMPLE 7 The procedure of Example 6 was repeated using B-(p-chloroanilino) propionitrile (20 g;) in place of ,B-(p-methylanilinb) propionitrile. Wt. of recrystallised B-(p-chloroanilino)-a-3,4,5-trimethoxybenzylacrylonitrile 24 g. (67 percent) m.p. 172l73C (recrystallised from methanol).

EXAMPLE 8 The procedure of Example 6 was repeated using B-(p-methoxyanilino) propionitrile (19.5 g.) in place of B-(p-methylanilino) propionitrile. Wt. of recrystallised B-(p-methoxyanilino)-a-3,4,5-trimethoxybenzylacrylonitrile 11 g. (33 percent) mp. 125-125C (recrystallized from methanol).

EXAMPLE 9 2-Methy1-4,5-dimethoxybenzaldehyde (18 g.), dimethylsulphoxide ml.), sodium methoxide (1.0 g.), and B-anilinopropionitrile were heated together at 95C for 1%hr. The mixture was then poured into icewater (150 g.), and the resulting solid collected by decantation. The crude product was recrystallised from methanol (100 ml.) and the resulting B-anilino-a-(Z- methyl-4,5-dimethoxybenzyl) acrylonitrile was collected, and washed with methanol of hexane. Wt. 19 g. (60 percent) m.p. l17119C (recrystallised from ethanol/methanol).

EXAMPLE l0 EXAMPLE 1] B-Morpholinopropionitrile (47 g.), sodium methoxide (2g. and dimethylsulphoxide (40 ml.) were heated together to 65C, and a solution of 3,4,5trimethoxybenzaldehyde g.) in dimethylsulphoxide (40 ml.) was added slowly such that the temperature rose to 7075C. After 3 min. at this temperature the mixture was cooled to 30C, and isopropyl alcohol (30 ml.) and water sufficient to creat a persistent haze were added. The mixture was seeded and, after crystallisation was obvious, water (80 ml.) was added. Crystalline Bmorpho1in0-a-3,4,5-trimethoxybenzylac rylonitrile was collected and washed with isopropyl alcohol (50 m1. Wt.

= 73.5 g. (89 percent) m.p. 1151 17C (recrystallised from methanol).

EXAMPLE 12 3,4,5-Trimethoxybenzaldehyde (20 g.), 13-N- methylanilinopropionitrile (18 g.), dimethylsulphoxide (40 ml.), and sodium methoxide (1 g.) were heated together at 110-115C for 1.5 hr. The mixture was poured into ice-water (800 ml.) and the crude product which precipitated gave crystalline B-N-methylanidinoa-3,4,5-trimethoxybenzylacrylonitrile after a slurry in methanol (50 ml.) 17 g. (50 percent) m.p. 1 21122C (recrystallised from methanol).

EXAMPLE 13 s 3 ,4,5-Trimethoxybenzaldehyde (50 g. B-piperidinopropionitrile (40 g.), di-methylsulphoxide ml.), and sodium methoxide (2 g.) were reacted to- V gether at 75C for 20 min. and on work-up gave B-piperidino-a-B,4,5-trimethoxybenzylacrylonitrile. Wt.=40 g. (50 percent) m.p. 92-93C (recrystallised from methanol).

EXAMPLE 14 3,4,5-Trimethoxybenzaldehyde (25 g.), B-pyrrolidinopropionitrile (20 g.), dimethylsulphoxide (25 ml.) and sodium methoxide (1 g.) were reacted together at 75C for 10 min., and on work-up gave B-pyrrolidino-a-3,4,5-trimethoxybenzylacrylonitrile.

Wt.=28 g. percent) m.p. 123-124C (recrystallised from methanol).

EXAMPLE 1 5 '3,4,S-Trimethoxybenzaldehyde (25 g.), B-N-dimethylaminopropionitrile (16 g. dimethylsulphoxide (45 ml.), and sodium methoxide (1 g.) were reacted to gether at 70C for 10 min., and on work-up gave B-dimethylamino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=25 g. (73 percent) m.p. l22l23C (recrystaL lised from methanol).

EXAMPLE 16 3,4,5-Trimethoxybenzaldehyde (50 g.), B-benzylaminopropionitrile (45 g.), dimethylsulphoxide ml.), and sodium methoxide (2 g.) were heated together at 100C for 2 hr., and on work-up gave B-benzylamino-a-3,4,S-trimethoxybenzylacrylonitrile. Wt.=32 g. (37 percent) m.p. 130.5-l3lC (recrystallised from methanol).

EXAMPLE 17 3,4,S-Trimethoxybenzaldehyde (25 g.), B-morpholinopropionitrile (20 g.), sodium methoxide (2 g.), and N,N-dimethylacetamide (25 ml.) were reacted together at 95C for 1% hr., and on work up gave l fl-morpholino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.= g. (37 percent).

EXAMPLE l8 EXAMPLE 19 The procedure of Example 18 was repeated using B-dimethylaminopropionitrile (28 'g.) in place of B-morpholinopropionitrile, and on work-up gave B-dimethylamino-a-3,4-dimethoxybenzylacrylonitrile. Wt.=31 g. (50 percent) m.p. 8586C (recrystallised from methanol).

EXAMPLE 20 B-Morpholinopropionitrile (20 g.), dimethylsulphoxide (30 ml.), and sodium methoxide (1 g.) were heated together at 80C and a solution of piperonaldehyde (19 g.) in dimethylsulphoxide was added. The mixture was reacted at 80C for 15 min., and on workup gave B-morpholino-a-piperonylacrylonitrile. Wt.=21 g. (61 percent) m.p. 85-85.5C (recrystallised from methanol).

EXAMPLE 21 The procedure of Example 20 was repeated using 3,-

4-dimethoxy-5-bromobenzaldehyde (31 g.) in place of piperonaldehyde and on work-up gave fi-morpholino- 04-3,4-dimethoxy-5-bromobenzylacrylonitrile. Wt.=28 g. (60 percent) m.p. 94.595C (recrystallised from denatured ethanol).

EXAMPLE 22 B-Hydroxy-a-3,4,5-trimethoxybenzylacrylonitrile (132 g.), obtained'as hereinafter described in Example 62, was refluxed for 10 min. in benzene containing aniline (50 g.). The solvent was removed by evaporation in vacuo to provide crystalline B-anilino-a-3,4,5- trimethoxybenzylacrylonitrile (165 g.; virtually theoretical yield).

EXAMPLE 23 A solution of morpholine (10 ml.) and ,B-hydroxy-a- 3,4,5-trimethoxybenzylacrylonitrile (24.9 g.) in ethanol 100 ml.) was refluxed for 30 min. When cooled the reaction gave B-morpholino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=27 g. (85 percent) m.p. 116117C.

EXAMPLE 24 B-Hydroxy-B-3,4,5-trimethoxyphenethylmethylsulphone (29 g.), B-anilinopropionitrile (16.5 g.), and dimethylsulphoxide (40 ml.) were heated together to 40C, and a solution of potassium-t-butoxide in tbutanol (13.6 percent; 83 ml.) was carefully added. The temperature was maintained at 45C for 1 hr. Alcohol was then removed from the reaction mixture by vacuum evaporation and the residue was poured into ice-water (200 ml.). The crude crystalline product was collected and recrystallised from ethanol to give B-anilino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=26 g. (after washing with ethanol and hexane; percent).

EXAMPLE 25 The procedure of Example 24 was repeated using hexamethylphosphoramide (40 ml.) in place of dimethylsulphoxide, and on work-up B-anilino-a-3,4,5- trimethoxybenzylacrylonitrile was obtained. Wt.=26 g. (80 percent) mp. 126128C.

EXAMPLE 26 B-Hydroxy-B-3,4,5-trimethoxyphenethylmethylsulphone (5 g.), B-anilinopropionitrile (3 g.) dimethylsulphoxide (20 ml.), and a solution of potassium hydroxide in methanol (20 percent 2 ml.) were reacted together at 95C for 20 min. Work-up gave B-anilino-a-3,4,5-trimethoxybenzylacrylonitrile (3 g.; 53 percent). m.p. 126-129C (recrystallised from ethanol).

EXAMPLE 27 The procedure of Example 26 was repeated using hexamethylphosphoramide (20 ml.) in place of dimethylsulphoxide and on work-up gave B-anilino-a-3,4,5- trimethoxybenzyl-acrylonitrile (2 g.; 36 percent) m.p. l25l27C (recrystallised from ethanol).

EXAMPLE 28 The procedure of Example 26 was repeated using sodium methoxide (0.5 g.) in place of potassium hydroxide in methanol, and on work-up gave B-anilino-a- 3,4,5-trimethoxybenzylacrylonitrile. Wt.=3 g. (54 percent) m.p. l28l30C.

EXAMPLE 2 9 B-Hydroxy-B-3,4,S-trimethoxyphenethylmethylsulphone (10 g.), B-anilinopropionitrile (5.1 g.) hexamethylphosphoramide (20 ml.), and sodium methoxide (1 g.) werereacted together at 60C for 30 min., and on work-up gave B-anilino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=6 g. (54 percent) m.p. 127-129C.

EXAMPLE 30 The procedure of Example 28 was repeated using N,N-dimethylacetamide (25 ml.) in place of dimethylsulphoxide, and on work-up gave B-ani1ino-a-3,4,5-

.trimethoxybenzylacrylonitrile. Wt.=2.5 g. (45 percent) mp. -128C.

EXAMPLE 31 B-Hydroxy-B-3,4,5-trimethoxyphenethylmethylsul phoxide (5.4 g.), B-anilinopropionitrile (3 g.), dimethylsulphoxide (25 ml.), and sodium methylate (0.5 g.) were reacted together at 9095C for 1 hr. The mixture was then poured into ice-water; the solid collected; and recrystallised from denatured ethanol to give B-anilino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2 g. (30 percent) m.p. l25l27C.

EXAMPLE 32 The procedure in Example 31 was repeated-using po tassium hydroxide (2 g.) in methanol (5 ml.) in place of sodium methoxide, and on work-up gave B-anilinoa-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2 g. (30 percent) m.p. l25128C.

EXAMPLE 33 The procedure in Example 31 was repeated using hexamethylphosphoramide in place of dimethylsulphoxide and sodium methylate (2 g.), and on work-up gave fi anilino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2 g. (30 percent) m.p. l25-129C.

EXAMPLE 34 The procedure in Example 31 was repeated using potassium-t-butoxide in t-butarol (13.6 percent; ml.) in place of sodium methoxide, and on work-up gave B-anilino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=1 g. (15 percent) m.p. 128130C.

EXAMPLE 35 The procedure in Example 34 was repeated using hexamethylphosphoramide (25 ml.) in place of dimethylsulphoxide, and on work-up gave B-anilino-a-3,4,5- trimethoxybenzylacrylonitrile. Wt.= l g. (15 percent) m.p. 123-126C.

EXAMPLE 36 B-Morpholinopropionitrile (3.0 g.) B-hydroxy-B- 3,4,5-trimethoxyphenethylmethylsulphone (2.9 g.), sodium methoxde (0.3 g.) and hexamethylphosphoramide (6 ml.) were reacted together at 60-65C for 40 min., and then poured into ice-water (50 ml.). The crude solid was collected by decantation and recrystallised from ethanol (10 ml.) to give B-morpholino-a- 3,4,5-trimethoxybenzylacrylonitrile. Wt.=2 g. 60 percent).

EXAMPLE 37 The prodecure in Example 36 was repeated using benzyltrimethylammonium hydroxide in place of sodium methoxide and on work-up B-morpholino-oz- 3,4,5-trimethoxybenzylacrylonitrile was obtained in 50 percent yield.

EXAMPLE 38 crystallisation was obvious. Filtration gave B-anilino-a- 3,4,5-trimethoxybenzylacrylonitrile. Wt.=296 g. (after washing with water and isopropanol; 91 percent.

EXAMPLE 41.

Aniline hydrochloride, from aniline 10 g.) and cone. hydrochloric acid (12 ml. and fi-morpholino-a-3,4,5-

' trimethoxybenzylacrylonitrile (30 g.) were reacted to- 3,4,5-Trimethoxybenzaldehyde (40 g.), B-anilinopropionitrile (44 g.), sodium methoxide (32 g.), and methanol were heated together underreflux for 45 min. The reaction mixture was then poured into icewater (200 ml.) and the resulting thick oil was collected and washed by decantation. Recrystallisation from ethanol gave crystalline B-anilino-a-3,4,5- trimethoxybenzylacrylonitrile. Wt.=42 g. (after washing with ethanol and pentane; 64 percent).

EXAMPLE 39 3,4-Dimethoxybenzaldehyde (41.5 g.), B-anilinopropionitrile (38.5 g.) sodium methoxide (40 g.) and methanol (200 ml.) were reacted under reflux for 3 hr. The solvent was then removed by evaporation in vacuo and the resulting paste was recrystallised from methanol to give B-anilino-a-3,4,-dimethoxybenzylacrylonitrile. Wt.= g. (75 percent) m.p. 153154C (recrystallised from ethanol).

EXAMPLE 4O B-Morpholino-a-Zl,4,5-trimethoxybenzylacrylonitrile v (318 g.), aniline (107 g.) and glacial acetic acid (69 g.) were heated together at 95C for 45 min. Isopropanol (300 ml.) was then added and the mixture was cooled to 30C; seeded; and treated with water (300 ml.) after gether in refluxing isopropanol (50 ml.) for 15 min. Water (25 ml.) was added and on cooling crystals of ,B-anilino-a3,4,5-trimethoxybenzylacrylonitri1e were obtained. Wt.=29 g.

EXAMPLE 42 EXAMPLE 43 3,4,5-Trimethoxybenzaldehyde (25 g.), B-morpholinopropionitrile (20 g.), methanol (50 ml.), and sodium methoxide (1 g.) were heated together under reflux for 72 hr. Solvent was then removed in vacuo and the residue was crystallised fro m diethylether (100 ml.) to give ,G-morpholino-a-3,4,5-trimethoxybenzylidenepropionitrile. Wt.=18 g. (44 percent) rn.p. l00.5102C (recrystallised from methanol).

EXAMPLE 44 3,4-Dimethoxybenzaldehyde (21 g.), B-morpholinopropionitrile (22 g.), sodium methylate (1 g.) and methanol (50' ml.) were heated together under reflux for 20 hr. Work-up as in Example 43 gave B-morpholino-a-3,4-dimethoxybenzylidenepropionitri1e. Wt.=25 g. (67 percent) m.p. -97C. (recrystallised from methanol).

EXAMPLE 45 The procedure of Example 43 using B-piperidinopropionitrile (20 g.) gave B-piperidino-a-3,4,5-

trimethoxybenzylidenepropionitrile. Wt.=32 g. (79

percent) m.p. 6062C (recrystallised from isopropanol).

EXAMPLE 46 The procedure of Example 43 using B-pyrrolidinopropinitrile (20 g.) gave B-pyrrolidino-a-3,4,5-

trimethoxybenzylidenepropionitrile as an oil. Wt.= 37' g. (96 percent).

EXAMPLE 47 The procedure of Example 43 using B-dimethylaminopropionitrile (18 g.) gave B-dimethylaminoa-3,4,5-trimethoxybenzylidenepropionitrile. Wt.=20 g. (57 percent) m.p. 8 l-83C (recrystallised from methanol).

EXAMPLE 48 Piperonaldehyde (30 g.), l3-morpholinopropionitrile (40 g.), methanol (75 ml.) and sodium methylate (1.5 g.) were heated together under reflux for 20 hr. Solvent was removed in vacuo and the residue recrystallised from ether, after treatment with aqueous sodium bisulphite, to give B-morpholino-apiperonylidenepropionitrile. Wt.=29 g. (53 percent) m.p. 8085C. (recrystallised from methanol).

EXAMPLE 49 B-Morpholino-a-3,4,5-trimethoxybenzylidenepropionitrile (3 g.), dimethylsulphoxide (10 ml.) and sodium methoxide (0.1 g.) were heated together at 5060C for 10 min. Work-up gave crystalline B-morpholino-a-3,4,5-trimethoxybenzylacrylonitrile. m.p. lll17C.

EXAMPLE 50 The procedure of Example 49 was repeated using B-dimethylamino-a-3,4,5-trimethoxybenzylidenepropionitrile (4 g.) and on work-up gave B-dimethylaminm a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=3.2 g. (80 percent) m.p. ll9l22C (recrystallised from methanol).

EXAMPLE 5 l The procedure of Example 49 was repeated using B-piperidino-a-3,4,5-trimethoxybenzylidenepropionitrile (3.5 g.) and in work-up gave B-piperidino-a-3,4,5- trimethoxybenzylacrylonitrile. Wt.=2.7 g. (77 percent) m.p. 8992C.

EXAMPLE 52 EXAMPLE 53 B-Dimethylam'ino-a-S,4,5-trimethoxybenzylidenepropionitrile (2 g.), dimethylsulphoxide ml.) and potassium-t-butoxide (0.05 g.) at 30 for 1 min. gave B-dimethylamino-a-3 ,4,5-trimethoxybenzylacrylonitrile. Wt.=l g. (50 percent m.p. 119l21C.

EXAMPLE 54 B-Dimethylamino-a-3,4,5-trimethoxybenzylidenepropionitrile (4 g.), hexamethylphosphoramide (10 ml.), and potassium-t-butoxide (0.05 g.) at 30C for 1-2 min. gave B-dimethylamino-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=3 g. (75 percent) m.p. ll7ll9C.

EXAMPLE 55 B-Dimethylamino-a-3,4,5-trimethoxybenzylidenepropionitrile (2 g.), dimethylsulphoxide (10 ml.), and 3 drops of a saturated solution of potassium hydroxide in methanol at 40C for 5 min. gave B-dimethylaminoa-3,4,5-trimethoxybenzylacrylonitrile Wt.=l.3 g. (65 percent) m.p. l 18l20C.

EXAMPLE 56 The procedure as in Example 55 using hexamethylphosphoramide in place of dimethylsulphoxide in 2 min. gave B-dimethylamino-a-3,4,5-trimethoxybenzylacrylonitrile Wt.=l.8 g. (90 percent) m.p. l2l123C.

EXAMPLE 57 The procedure as in Example 49 using B-pyrrolidinoa-3,4,5-trimethoxybenzylidenepropionitrile gave B-pyrrolidino-a-3,4,5-trimethoxybenzylacrylonitrile. m.p. 123-l 24C.

EXAMPLE 58 The procedure as in Example 52 using B-morpholinoa-3,4-dimethoxybenzylidene propionitrile gave B-morpholino-a-3,4-dimethoxyacrylonitrile. l 27l 29C.

EXAMPLE 59 The procedure as in Example 49 using B-morpholinoa-piperonylid nepropionitrile (5.0 g.) gabe B-morpholino-a-piperonylacrylonitrile. Wt.=4.5 g. (90 percent) m.p. 80-84C.

EXAMPLE 60 The procedure as in Example 50 using N,N- dimethylacetamide in place of dimethylsulphoxide gave ,B-dimethylamino-a-El ,4,5 -trimethoxybenzylacrylonitrile in 83 percent yield. m.p. l2l-l23C.

EXAMPLE 61 The procedure as in Example 52 using benzyltrimethylammonium hydroxide in place of sodium methoxide gave B-dimethylamino-a-3,4,5-trimethoxybenzylacrylonitrile in 86 percent yield. m.p. 122123C.

EXAMPLE 62 B-Morpholino-a-3,4,5-trimethoxybenzylacrylonitrile (157 g.) was treated with cone. hydrochloric acid ml.) in water (180 ml.) at 60C for l5 min. The reaction mixture was cooled, extracted with chloroform (100 ml.; 75 ml.; 75 ml.), and the extracts were backwashed with water 75 ml.). Removal of solvent gave B-hydroxy-a-3,4,5-trimethoxybenzylacrylonitrile as a thick oil. Wt.=l25 g. (theory).

EXAMPLE 63 B-Hydroxy-a-3,4,5-trimethoxybenzylacrylonitrile (70 g.) in methanol (150 ml.) at 10C was treated with dimethylsulphate (39 g.). To the mixture was then gradually added a solution of potassium hydroxide (20 v g.) in methanol (30 ml.) and water 12 ml.) and the reaction was then kept at 10C for 15 min. The mixture was next heated to 60C for 15 min; then cooled, and finally solvent was removed to a residue which was slurried in water (100 ml.) and extracted into chloroform (2 X ml.). The chloroform extract, after backwashing with water (.70 ml.), drying, and treatment with charcoal, was evaporated to dryness to give B-methoxy-a-3,4,5-trimethoxybenzylacrylonitrile. Wt.=6l g.

(80 percent).

EXAMPLE 64 B-Anilino-a-3 ,4,5-trimethoxybenzylacrylonitrile (32 g.) and a solution of guanidine hydrochloride (19 g.) and sodium methoxide (13 g.) in denatured ethanol ml.) were heated under reflux for 2% hr. Solvent (3l ml.) was boiled off and the mixture was cooled to 5C. The resulting crystals of 2,4-diamino-5-(3,4,5'-

trimethoxybenzyl)pyrimidine were collected and washed with denatured ethanol and acetone. Wt.=27 g. (94%) mp. 198200C.

Using methanol in place of denatured alcohol gave 2,4-diamino--(3,4,5-trimethoxybenzyl)pyrimine in 86 percent yield after 6 hr. reflux; with isopropanol the reaction was over in 2 hrs. and the yield was 78 per cent.

EXAMPLE 65 the product from Example 6 was converted to 2,4- diamino-5-( 3 ,4,5 '-trimethoxybenzyl )pyrimidine by the procedure of Example 64 in 2 hr. Yie1d=90 percent.

EXAMPLE 66 The product from Example 7 was converted to 2,4- diamino-5-( 3 ,4,5 '-trimethoxybenzyl )pyrimidine by the procedure of Example 64 in 2 hr. Yield=90 percent.

EXAMPLE 67 The product from Example 8 was converted to 2,4- diamino-5-( 3 ,4,5 -trimethoxybenzyl )pyrimidine the procedure of Example 64 in 4% hr. Yield=90 percent.

EXAMPLE 68 The procedure of Example 64 was repeated using B-anilino-a-3,4-dimethoxybenzylacrylonitrile (29.4 g.) and gave 2,4-diamino-5-(3',4-dimethoxybenzyl)- pyrimidine. Wt.=25.5 g. (98 percent) m.p. 230233C.

EXAMPLE 69 The procedure of Example 64 was repeated using B-anilino-a-piperonylacrylonitrile (28 g.) and gave 2,4- diamino-5-piperonylpyrimidine. Wt.=22 g. (89.5 percent) m.p. 252253C (recrystallised from denatured alcohol).

EXAMPLE 70 The procedure of Example 64 was repeated using B-anilino-a-2 -methyl-4,5-di-methoxybenzylacrylonitrile (16 g.) and after 18-20 hr. reflux gave 2,4- diamino-5-(2-methyl-4' ,5 -dimethoxybenzyl)pyrimidine. Wt.=1 1.5 g. (92 percent) m.p. 230231C.

*EXAMPLE 71 The procedure of Example 64 was repeated using B-anilino-a-3 ,4-dimethoxy-5 -bromobenzylacrylonitrile (62 g.) and gave 2,4-diamino-5-(3,4'-dimethoxy-5'- bromobenzyl)pyrimidine. Wt.=38 g. (70 m.p. 203.5-205C.

EXAMPLE 72 The procedure of Example 64 was repeated using B-anilino-a-p-benzyloxybenzylacrylonitrile (25 g.) and gave after 4 hr. reflux 2,4-diamino-5-(p-benzyloxybenzyl)pyrimidine. Wt.=20.5 g.. This was converted to its acetate salt by treatment with acetic acid. Wt.=l5 g.

EXAMPLE 73 2,4-Diamino-5-(p-benzyloxybenzyl-pyrimidine acetate (4.6 g.) in methanol (200 was hydrogenated at low pressure over 5 percent Palladium/Carbon. The filtrate after removal of catalyst was evaporated and the resulting residue purified by dissolution in hot dilute acetic acid and re precipitation with ammonium hydroxide to pH 9. Crystalline 2,4-diamino-5-(phydroxybenzyl)- pyrimidine was collected" and washed with water.

Wt.=2.16 g. m.p. 300 303c.

EXAMPLE 74 B-Morpholino-a-3,4,S-trimethoxybenzylacrylonitrile (32 g.), guanidine carbonate (34 g.) and dimethylsulphoxide (50 ml.) were heated together at 160C. for 1 hr. with good stirring. The reaction mixture was cooled and poured into ice-water (200 ml and gave 2,4- diamino-5-( 3 ,4,5 -trimethoxybenzyl )pyrimidine which was collected and washed with water and acetone. Wt.=23.6 g. (80 percent) m.p. l96198C.

EXAMPLE 75 The procedure of Example 74 was repeated using [3-N-methylanilino'a-3,4,5-trimethoxybenzylacrylonitrile and gave 2,4-diamino-5-(3',4',5-trimethoxybenzyl)pyrimidine. 1

EXAMPLE 76 The procedure of Example 74 was repeated using /3-piperidino-a-3,4,5 -trimethoxybenzylacrylonitrile and gave 2,4-diamino-5-(3,4,5'-trimethoxybenzyl)- pyrimidine.

EXAMPLE 77 The procedure of Example 74 was repeated using B-pyrrolidino-a-3,4,S-trimethoxybenzylacrylonitrile and gave 2,4-diamino-5-(3,4,5-trimethoxybenzyl)- pyrimidine.

EXAMPLE 78 EXAMPLE 81 The procedure of Example 74 was repeatedusing B-dimethylamino-a-3,4-dimethoxybenzylacrylonitrile and gave 2,4-diamino-5-(3',4'-dimethoxybenzyl)- pyrimidine.

EXAMPLE 82 The procedure of Example 74 was repeated using B-morpholino-a-piperonylacrylonitrile and gave 2,4-

diamino-S-piperonylpyrimidine.

-trimethoxybenzylacryloni- EXAMPLE 83 The procedure of Example 74 was repeated using B-morpholino-a-3,4,-dimethoxy-- bromobenzylacrylonitrile and gave 2,4-diamino-5- (3 ,4-dimethoxy-5 -bromobenzyl) pyrimidine.

EXAMPLE 84 The procedure of Example 64 was repeated using The procedure of example 64 was repeated using the products of ex. 85 to give 2,4-Diamino-5(3',4- dichlorobenzyl) pyrimidine, m.p. 237-23 9, 2,4-Diamino-5-(o-iodobenzyl) pyrimidine, m.p.

265-267, 2,4-Diamino-5-(m-iodobenzyl) pyrimidine, m.p. 220.5222, 2,4-Diamino-5-(p-iodobenzyl) pyrimidine, m.p. 246248, and 2,4-diamino-5-(obromobenzyl) pyrimidine, m.p. 248250.

EXAMPLE 8? B-hydroxy-a-3,4,5-trimethoxy-benzylacrylonitrile 25 grams, denatured ethanol (70 ml.) 2,4-dimethyl aniline 14 ml.) refluxed together for 1 hr. Solvent removed by evaporation and vacuum and the residue was'poured into ice water. The resulting thick gum was collected and recrystallized from methanol to give crystaline B-ZA-dimethylanidino -a-3,4,5-trimethoxybenzylacrylonitrile. Wt. =l1g. (31 percent yield) M.P. 123l25 C.

EXAMPLE 88 Procedure of Example 87 was repeated using 3,4,5-

trimethoxyaniline and gave [3-3,4,5-trimethoxybenzylacrylonitrile in 65 percent yield. M.P. 156 -l6lC. Recrystallized from denatured ethanol.

EXAMPLE 89 Procedure of Example 87 was repeated using 2,5- dichloroaniline-and gave B-2,5,-dichloroariilino -a-3,4,- 5-trimethoxybenzylacrylonitrile. 20 g, 51 percentyield. A sample recrystallized from denatured ethanol melted at 130 C, resolidified, and then remelted at 150C."

EXAMPLE 90 Procedure of Example 87 was repeated using anapthylamine 14.3gr. and gave crystaline B-lnapthylamino -a-3,4,5-trimethoxybenzylacrylonitrile. Wt. =26 gr. 70 percent yield, melting pt. l07 109C.

EXAMPLE 91 The product from Example 87 was converted to trimethoprim by the procedure of Example 64 in 4 hrs. Yield 92 percent.

EXAMPLE 92 The product from Example 88 was coverted to trimethoprim by the procedure of Example 64 in 3 hrs. Yield above 90 percent.

EXAMPLE 93 The product from Example 89 was converted to trimethoprim by the procedure of Example 64 in 1.5 hrs. Yield95 percent. This reaction was repeated as in Example 64 except at room temperature and useful yield of trimethoprim was obtained in several hrs.

EXAMPLE 94 The product from Example 90 was converted to trimethoprim by the procedure of Example 64 in several hrs. Yield 72 percent.

. EXAMPLE 95 Methyl a-(3,4,S-trimethoxyacetophenone) Sulphone Charge into a 500 ml. three necked flask equipped withstirrer and reflux condenser, 27 gms. (0.69M) so-- dium amide, 225 ml. dimethylsulphoxide and 56.5 gm. dimethylsulphone (0.6M). l-leat to 55C for one hour with stirring, and cool to 50C. Add 65.4 gm. (0.29M) 3,4,5-trimethoxymethylbenzoate and heat to 60C for one hour to complete the reaction.

Pour the mixture onto 1100 gm. of ice and acidify with 180 ml. dilute HCl (1:1). Cool in an ice bath and filter the crystalline product. Wash with 2 l50 ml. of ice water and 2Xl00 ml. ice cold lower alcohol such as ethanol. Air dry overnight or vacuum dry at 40C to constant weight. The yield will be 74 gm. or 88 percent of theory of suitable intermediate for the next step. A.N. Sample M.P. l47l48C. Recrystallized from Ethanol Calculated Found C 49.98 49.8 H 5.59 5.54

EXAMPLE 96 Reduction of methyl a(3,4,5-

trimethoxyacetophenone) sulphone to the corresponding alcohol Set up a 3 neck 1 liter flask equipped with a stirrer in an ice bath. Charge with 38.] gm. of methyl a(3,4,5- n trimethoxyacetophenone) sulphone, 100 ml. desalted water and 30 ml. ethanol and cool this slurry to +1 5C. Add portion wise a precooled solution of 2 gm. sodium borohydride in 40 ml. desalted water. The first few ml. will cause a slight foaming but it can be controlled easily with a few ml. of ethanol. Additional ethanol can be Found Calculated C ,49.7 49.39 H 6.24 6.27

EXAMPLE 97 m-(methylsulfinyl)3,4,5-Trimethoxyacetophenone Into a three necked flask, equipped with condenser, stirrer and thermometer, charge 4.0 gm. sodium amide (hexane washed) and 75 ml. dimethyl sulphoxide (distilled and dried). Slowly warm (in an externalwater bath) to 45C and the reaction begins. Raise temperature gradually to 60C and maintain for one (1) hour, to complete.

Cool to +15 and add dropwise a solution of 12 gm. 3,4,5-trimethoxymethylbenzoate in 25 ml. of dimethylsulphoxide. Keep the temperature between 20-25C by external cooling. Stir one-half hour at room temperature and quench into 300 ml. ice water. Carefully acidify to pH 6 with cold dilute hydrochloric acid.

Extract into chloroform 3X100 ml. wash the organic layer with 4X50 ml. water, dry over sodium sulfate, filter and flash evaporate all solvent.

The heavy oil will weigh 15 gm. and slowly crystallize on standing.

To purify; dissolve the thick oil in 75 ml. ethyl acetate, charcoal and cool the filtrate in an ice acetone bath. Filter and dry the white solid. Wt. gm z 70 percent yield. M.P. ll3l15C.

A.l\l. Sample M.P. ll5l 16C Recrystallized from acetone Calculated Found 7 C 53.05 52.69 H 5.92 5.84

EXAMPLE 98 BHydroxyB3,4,S-trimethoxyphenethylmethylsulphoxide I OH 01-1.. 0 JJCH2 s 0 --CH3 it onto Combine 14 gm. w( methylsulfinyl)3,4,5-

trimethoxyacetophenone, 50 ml. desalted water and 35 ml. methanol. Cool to +15C and with magnetic stirring add slowly a solution of 0.5 gm. sodium borohydride in 10 ml. water. The reaction is exothermic but can be controlled between 15 C with external cooling.

Stir at room temperature for 2 hours, check for completion by U.V. and finally strip off methanol by vacuum at 45 50C.

Extract the aqueous solution with 3X75; ml. chloroform, wash with the organic layer 1X75ml. water, dry over magnessium sulphate, filter and evaporate to a clear thick oil. A few drops of ethyl acetate causes complete crystallization. Weight 14 gm. This is suitable for use in the next step without further purificatlon.

A.N. Sample M.P. l50-l55C (lsomers) Recrystallized from Ethyl Acetate.

. Calculated Found* C 52.4 52.37 H 6.61 6.70

EXAMPLE 99 a(3.4,5-Trimethoxylbenzyl) B-anilinoacrylonitrile ctno CHNIlPlt cm-o (1N cino Combine in a'flask at room temperature 5.4 gm. B-hydroxy-B-3,4,5-trimethoxyphenethyl methyl sulphoxide, 3 gm. B-anilinopropionitrile, 25 ml. dimethylsulphoxide and 2.0 gm. sodium methylate. Warm slowly with stirring, on a steam bath up to 95C. It gets very dark in color. Reaction, by U.V., is complete in 20 minutes at C.

Quench in ice water and wash the dark oily precipitate by decantation. Dissolve in 15 ml. of ethanol and cool. Filter the heavy yellow crystalline precipitate, wash with cold ethanol and hexane. Dry. Wt. 2 gm. 3 1% yield. The U.V., l.R., and MP. are identical to that prepared from the 3,4,5-trimethoxybenzaldehyde and B-anilinopropionitrile Ph =phenyl.

*Hexamethylphosphoramide has been substituted for the dimethyl sulphoxide as well as potassium hydroxide in methanol for the sodium methylate with the same results in all cases.

EXAMPLE a (3,4,5- tri-methoxybenzyl)-B-anil.inoacrylonitrile orno | CHNHPh N 0 CH3 0 'Strip as much alcohol as possible by vacuum using an external water bath (70C) and quench in ice water (200 ml.). Stir until the thick oil turns crystalline and filter. Wash the cake with ice water and finally hexane.

Vacuum dry at 35C to constant weight. The yield will crudea- The be 32 gm. or theory of (3 ,4,5trimethoxybenzyl-B-anilinoacrylonitrile U.V. is satisfactory and it may be used directly in the preparation of Trimethoprim.

* Recrystallisation Dissolve the crude intermediate in 75 ml. hot ethanol. Cool in ice/acetone bath (preferably overnight) and filter. Wash the cake with cold ethanol (15 ml.) and hexane. Vacuum dry. Weight 26+ gm. 80 percent yield.

EXAMPLE lOl Trimethoprim 2,4-diamino--( 3 ,4,5 trimethoxybenzyl) pyrimidine Prepare a guanidine solution from gm. guanidine HCl, 10 gm. sodium methylate, and 100 ml. ethanol.

, Cool, filter salt free, and combine with 16 gm. a(3,4,5-

trimethoxybenzyl)B-anilinoacrylonitrile. Reflux on a steam bath overnight, charcoal the hot solution with 2.0 gm. Darco 6-60 and evaporate to one-fourth volv ume. Cool to complete crystallization, filter, and wash with cold ethanol, acetone, and ether. Dry. Weight 13+ gm.-91 percent theory. M.P. l98200C.

EXAMPLE 102 B-HydroxyB-3,4,5-trimethoxyphenethylmethylsulphoxide Sodium methylate (5.4 gm.) was dissolved in hot dimethylsulfoxide (50 ml.), the solution was cooled to room temperature, 3,4,5-trimethoxybenzaldehyde (18 gm.) was added, and the mixture was stirred at room temperature for 2 hours. Water (100 ml.) was then added to the mixture which was next extracted with chloroform. The chloroform extract was washed with water, dried over anhydrus sodium sulfate, and evapo-.

rated to dryness. The residual yellow oil crystallised on addition of ethylacetate. The crystals were collected and washed with pentane. Wt. 14.8 gm. (59 percent) M.P. 160162C (After recrystallisation from ethylacetate. IR. and UV. spectra in agreement with structure.

Calculated Found C 52.4 52.37 H 6.61 6.70 I

What we claim is: l. The method of preparing a compound of the formula (I) where R is lower alkyl or hydrogen, where R R are the same or different and each ishydrogen, halogen, lower alkyl, lower alkoxyl or benzyloxy, or R and R taken together may be methylenedioxy when both R and R are hydrogen, where Ph is aryl of 6 to 12 carbons which may be substituted in one, two, or three positions with lower alkyl, lower alhoxyl or halogen and in the above lower akoxyl and lower alkyl contain 1' to 4 carbon atoms which comprises reacting an acid addition salt of HNR Ph with a compound of the formula where the free amine of NR R has a PKa of about 3 or more units higher than that of the free amine of NR Ph,

andR R are as defined above, and NR R is an aliphatic, aromatic or cyclic amino group containingnot more than 12 carbon atoms.

2. The method according to claim 1 wherein NR R is morpholino R is hydrogen and Ph is phenyl.

3. The method according to claim 2 in which one of R R is hydrogen and the others are methoxyl at the 3,4 and 5 positions of the ring.

4. The method according to claim 3 in which the reaction is carried on in a polar non-aqueous solvent with heat.

5. The method according to'claim 4 wherein the solvent is a lower alkanol of 1 to 4 carbons or a lower car- 9. In the method of claim 7 in which the reactants are heated.

10. In the method of claim 8 in which the reactants are heated.

11. The method of claim 1 wherein NR R is selected from the class consisting of monoalkylamino, benzylamino or naphthylamino' 12. The method of claim 1 wherein NR R is selected from the class consisting of a-B-naphthylamino, pyrolidino, piperidino and piperazino.

13. The method of claim 1 wherein NR R is morphov 

1. THE METHOD OF PREPARING A COMPOUND OF THE FORMULA (I)
 2. The method according to claim 1 wherein NR5 R6 is morpholino, R0 is hydrogen and Ph is phenyl.
 3. The method according to claim 2 in which one of R1 - R4 is hydrogen and the others are methoxyl at the 3,4 and 5 positions of the ring.
 4. The method according to claim 3 in which the reaction is carried on in a polar non-aqueous solvent with heat.
 5. The method according to claim 4 wherein the solvent is a lower alkanol of 1 to 4 carbons or a lower carboxylic acid having 2-4 carbons.
 6. In the method of preparing Beta -anilino- Alpha -3,4,5-trimethoxybenzylacrylonitrile which comprises reacting an acid addition salt of aniline and Beta -morpholino- Alpha -3,4,5-trimethoxyacrylonitrile in a non-reactive solvent for the reactants.
 7. In the method of claim 5 wherein the solvent is a lower alkanol of 1 to 4 carbon atoms or a lower carboxylic acid having 2-4 carbon atoms.
 8. In the method of claim 6 wherein the solvent is a polar non-aqueous solvent.
 9. In the method of claim 7 in which the reactants are heated.
 10. In the method of claim 8 in which the reactants are heated.
 11. The method of claim 1 wherein NR5R6 is selected from the class consisting of monoalkylamino, benzylamino or naphthylamino.
 12. The method of claim 1 wherein NR5R6 is selected from the class consisting of Alpha - Beta -naphthylamino, pyrolidino, piperidino and piperazino.
 13. The method of claim 1 wherein NR5R6 is morpholino. 